Background
Phase III RCT (RTOG/ECOG Intergroup). 310 patients with epidermoid carcinoma of the anal canal. Compared RT + 5-FU alone vs RT + 5-FU + mitomycin C to determine the necessity of MMC in definitive CRT. RT: 45–50.4 Gy. 5-FU: 1000 mg/m²/d × 4 days during RT. MMC: 10 mg/m² on days 1 and 29 (2 doses). Also evaluated salvage chemoradiation (additional 9 Gy + 5-FU + cisplatin) in patients with residual disease on post-treatment biopsy.
Interventions and follow up
Arm A: RT (45–50.4 Gy) + 5-FU 1000 mg/m²/d × 4d (days 1–4 and 29–32)
Arm B: RT + 5-FU (same) + mitomycin C 10 mg/m² days 1 and 29
Primary endpoint: Colostomy rate, disease-free survival
mFollow up: 4 year
Arm B: RT + 5-FU (same) + mitomycin C 10 mg/m² days 1 and 29
Primary endpoint: Colostomy rate, disease-free survival
mFollow up: 4 year
Results
4-year colostomy rate: 22% (5-FU only) vs 9% (5-FU + MMC), P=.002
4-year colostomy-free survival: 59% vs 71%, P=.014
4-year DFS: 51% vs 73%, P=.0003
4-year OS: 67% vs 76%, P=.31 — not significant
Positive post-treatment biopsy: 15% (5-FU only) vs 7.7% (MMC), P=.135
4-year colostomy-free survival: 59% vs 71%, P=.014
4-year DFS: 51% vs 73%, P=.0003
4-year OS: 67% vs 76%, P=.31 — not significant
Positive post-treatment biopsy: 15% (5-FU only) vs 7.7% (MMC), P=.135
Adverse events
Main adverse events: Grade 4–5 toxicity: 7% (5-FU only) vs 23% (MMC arm), P≤.001. Most common: hematologic toxicity (leukopenia, thrombocytopenia). Salvage CRT in 24 assessable patients with residual disease: 50% rendered disease-free.
Conclusions
Despite greater toxicity, addition of mitomycin C to 5-FU–based CRT significantly improved colostomy-free survival and DFS in anal canal cancer, confirming MMC as an essential component of definitive CRT.
Key Limitations
Key Limitations: The trial demonstrated no OS benefit, likely due to inadequate power and the success of salvage therapy in residual disease cases. The significantly higher grade 4–5 toxicity with MMC has driven interest in replacing MMC with cisplatin or substituting 5-FU with capecitabine. RT doses were variable (45–50.4 Gy) without standardized boost protocol.
Clinical Context
The Intergroup trial established MMC as a required component of definitive CRT for anal cancer, leading to the current standard regimen of 5-FU + MMC + RT (~50.4 Gy). RTOG 9811 subsequently compared MMC-based CRT to cisplatin-based CRT, confirming MMC superiority. Capecitabine is increasingly used as an oral substitute for infusional 5-FU (Goodman IJROBP 2017).
References
References: Flam M et al, J Clin Oncol 1996 (Intergroup)